Autoxidative formation of a chemically reactive intermediate from amodiaquine, a myelotoxin and hepatotoxin in man

Maggs, James L.; Kitteringham, Neil R.; Breckenridge, AM; Park, B.K.

doi:10.1016/0006-2952(87)90130-4

Cited by 83 publications

(93 citation statements)

References 10 publications

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“…1. Proposed mechanism for the formation of chemically reactive intermediates from amodiaquine and hepatic amodiaquine metabolism (Maggs et al 1987a & b). dose amodiaquine treatment; activity of GSH S-transferase was decreased by 60% compared to control.…”

Section: Resultsmentioning

confidence: 99%

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Influence of Amodiaquine Treatment on Microsomal Lipid Peroxidation and Antioxidant Defense Systems of Rats

Farombi

2000

Pharmacology & Toxicology

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Abstract:The effects of single and multiple doses amodiaquine treatment on enzymatic and non-enzymatic antioxidant profiles and hepatic microsomal lipid peroxidation were investigated in rats. Treatment of rats with 10 mg/kg (single dose) amodiaquine resulted in 10% and 63% increases, respectively in the activities of liver superoxide dismutase and glutathione peroxidase (P∞0.01), while the activity of liver catalase was significantly reduced by 26% compared to control. The levels of serum vitamins A, C and b-carotene were lowered following amodiaquine treatment. Following multiple dose (10 mg/ kg for 4 consecutive days) amodiaquine treatment, activities of superoxide dismutase and glutathione peroxidase were increased by 30% and 133% respectively while catalase activity was decreased by 45%. Similarly, serum vitamins A, C and b-carotene levels were markedly decreased. In the single dose study, the levels of malondialdehyde and the activity of glutathione S-transferase were increased by 15% and 44% respectively while the reduced glutathione was decreased by 25% compared to control. Malondialdehyde level was highly increased (P∞0.001) by 71% following multiple amodiaquine treatment. Reduced glutathione was decreased by 55% and unlike in the single dose study, activity of glutathione Stransferase was decreased by 60% compared to control. The activities of serum aspartate amino transferase, alanine amino transferase, ornithine carbamyl transferase and g-glutamyl transferase were significantly increased by both single and multiple doses of amodiaquine treatment (P∞0.01). The alteration in enzymatic and non-enzymatic antioxidant defense system, increase in lipid peroxidation and increase in the activities of serum enzymes following amodiaquine treatment suggests damage to the liver and could subject the organ to further oxidative stress. The relevance of this to continuous exposure to amodiaquine therapy should be considered.

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Section: Resultsmentioning

confidence: 99%

“…1) (Wistanley et al 1987). Amodiaquine is metabolised by cytochrome P450-catalysed reaction forming an electrophilic metabolite, amodiaquine quinone imine, which can be conjugated with thiols like GSH or irreversibly binds to microsomal and soluble proteins (Maggs et al 1987a & b).…”

Section: Discussionmentioning

confidence: 99%

Influence of Amodiaquine Treatment on Microsomal Lipid Peroxidation and Antioxidant Defense Systems of Rats

Farombi

2000

Pharmacology & Toxicology

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“…Although it is still used in some countries, AQ was withdrawn from the market because of severe idiosyncratic drug reactions (IDR) that included hepatotoxicity (Larrey et al, 1986;Neftel et al, 1986), agranulocytosis (Rouveix et al, 1989), and aplastic anemia (Hatton et al, 1986). The mechanism of AQ-induced adverse reactions is currently not well understood, but AQ is metabolized to N-desethylamodiaquine (DEAQ) by CYP2C8 (Li et al, 2002), and both AQ or DEAQ can be oxidized to a reactive quinoneimine, which reacts with proteins to form covalent adducts (Maggs et al, 1987(Maggs et al, , 1988.…”

Section: Introductionmentioning

confidence: 99%

Development of a novel mouse model of amodiaquine-induced liver injury with a delayed onset

Metushi¹,

Cai

Dervovic

et al. 2014

Journal of Immunotoxicology

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Amodiaquine (AQ) treatment is associated with a high incidence of idiosyncratic drug-induced liver injury (IDILI) and agranulocytosis. Evidence suggests that AQ-induced IDILI is immune mediated. A significant impediment to mechanistic studies of IDILI is the lack of valid animal models. This study reports the first animal model of IDILI with characteristics similar to mild IDILI in humans. Treatment of female C57BL/6 mice with AQ led to liver injury with delayed onset, which resolved despite continued treatment. Covalent binding of AQ was detected in the liver, which was greater in female than in male mice, and higher in the liver than in other organs. Covalent binding in the liver was maximal by Day 3, which did not explain the delayed onset of alanine aminotransferase (ALT) elevation. However, coincident with the elevated serum ALT, infiltration of liver and splenic mononuclear cells and activation of CD8 T-cells within the liver were identified. By Week 7, when ALT levels had returned close to normal, down-regulation of several inflammatory cytokines and up-regulation of PD-1 on T-cells suggested induction of immune tolerance. Treatment of Rag1 À/À mice with AQ resulted in higher ALT activities than C57BL/6 mice, which suggested that the adaptive immune response was responsible for immune tolerance. In contrast, depletion of NK cells significantly attenuated the increase in ALT, which implied a role for NK cells in mild AQ-induced IDILI. This is the first example of a delayed-onset animal model of IDILI that appears to be immune-mediated.

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“…This drug binds to nucleoproteins of the parasites and inhibits its DNA and RNA polymerases (O'Neill et al, 1998). It generates free radicals in the form of AQ quinine immine and semi quinine immine which have been implicated in lipid peroxidation (Maggs et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

The effect of administration of amodiaquine on some Parameters of neurobehaviour of wistar rats

Ekong¹,

Igiri²,

Mesembe³

2010

Nig. J. Phys Sci

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Summary:The effect of administration of Amodiaquine (AQ) on some parameters of neurobehaviour of Wistar rats was carried out. Twenty adult Wistar rats weighing between 160-190g were divided equally into four groups. Group 1 served as the control, while groups 2, 3 and 4 were the experimental groups. The control group received distilled water. Groups 2 and 3 were treated with 8.75mg/kg and 17.50mg/kg respectively of AQ for three days, while group 4 was treated with 8.75mg/kg of AQ for six days. Neurobehaviour test using the open field was carried out twelve hours after the last administrations. There were no significant differences between the control and the experimental groups in total locomotor activity (TLA), central square duration (CSD), stretch-attend (SA) and defecation. In the central square frequency (CSF), group 3 was significantly (P<0.05) higher than all the groups, while the control was the same as group 4, but higher than group 2, with the difference not being significant. In conclusion, AQ increased TLA and exploration, while simultaneously reducing anxiety in Wistar rats and these were dose dependent.

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Autoxidative formation of a chemically reactive intermediate from amodiaquine, a myelotoxin and hepatotoxin in man

Cited by 83 publications

References 10 publications

Influence of Amodiaquine Treatment on Microsomal Lipid Peroxidation and Antioxidant Defense Systems of Rats

Influence of Amodiaquine Treatment on Microsomal Lipid Peroxidation and Antioxidant Defense Systems of Rats

Development of a novel mouse model of amodiaquine-induced liver injury with a delayed onset

The effect of administration of amodiaquine on some Parameters of neurobehaviour of wistar rats

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